1 / 64

Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy

Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy. The Women’s Health Initiative Randomized Controlled Trial JAMA 2004;291:1701-1712. Postmenopausal Hormone Use. Observational studies suggested 30%– 50% reduction in cardiac risk

keiko-justice
Download Presentation

Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy The Women’s Health Initiative Randomized Controlled Trial JAMA 2004;291:1701-1712.

  2. Postmenopausal Hormone Use • Observational studies suggested • 30%– 50% reduction in cardiac risk • 8% – 30% increase in breast cancer • Strong benefit for osteoporosis • In 1980’s – 90’s • Increasing use of hormone therapy for long-term cardiovascular disease prevention

  3. WHI Hormone TrialSpecific Aims • Primary Endpoint: To test whether CEE reduces the incidence of CHD and other CVD • Definition of CHD: Nonfatal MI plus CHD death • Primary Safety Endpoint: To assess whether CEE increases the risk of breast cancer • Secondary Endpoints: To test whether CEE reduces the incidence of hip fractures and all osteoporosis-related fractures separately

  4. Women’s Health InitiativeTimeline 1993 1998 1990 2005

  5. WHI Hormone Trial Design Conjugated equine estrogens (CEE) 0.625 mg/d Placebo E Alone N = 10,739 YES Hysterectomy NO CEE 0.625 mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/d E + P N=16,608 Placebo

  6. Eligibility • Age 50-79 years at first screen • Postmenopausal • Likely to reside in clinic area for at least 3 years • Providing written informed consent

  7. Severely underweight Severe hypertension (>200/105) Severe menopausal symptoms Substance abuse, mental illness, dementia History of: Cancer in last 10 years Melanoma any time Stroke or heart attack in last 6 months Previous fractures treated with hormones Any condition likely to limit survival < 3 yrs Excluded if: So these were generally healthy women and this was a primary prevention trial

  8. Follow-up Methods • 6 weeks after randomization: phone contact • Assess symptoms • Reinforce adherence • Every 6 months: phone or clinic contact • Assess adherence • Assess symptoms • Determine if outcomes had occurred • Annually: clinic visit • Mammograms + clinical breast exams • Assess adherence • Assess symptoms • Determine if outcomes had occurred

  9. Study Medication Use • Intolerable symptoms e.g., breast tenderness • Reduced number of days of treatment • No unblinding for management • Major event possibly related to hormones • Study meds stopped • Temporarily for fracture, immobilization, surgery • Permanently for breast CA, DVT/PE, malignant melanoma, meningioma, TG > 1000 mg/dl, if participant’s health provider prescribed open label hormones • Resumption up to participant’s health provider for MI or stroke • No unblinding for discontinuation of medications

  10. Ascertainment of Outcomes • Self report of diagnosis/hospitalization • Medical records obtained • Local WHI physician adjudicated (coded) events (blinded to treatment assignment) • Central adjudication (blinded to treatment assignment) • CHD • Stroke • VTE • Cancer • Hip fractures

  11. Events during the Hormone Trial • April 2000 – Participants notified of increase in CV events during first 2 years • July 2001 – Participants informed risk does not disappear after 2 years • July 2002 – • E+P trial intervention terminated due to increased breast cancer risk and overall risks exceeding benefits; Principal results published (JAMA 2002;288:331-333). • E alone trial is continued. • February 2004 – NIH terminates E-alone intervention due to increased stroke risk and absence of CHD benefit • March 1, 2004 – E- alone participants stop study pills

  12. Baseline Characteristics of women in the WHI Estrogen alone trial

  13. Age at entry

  14. Age of E-alone participants at entry Percent

  15. Race/Ethnicity Percent

  16. Age at hysterectomy

  17. Bilateral Oophorectomy

  18. History of Hormone Use

  19. Duration of prior hormone use

  20. Body Mass Index

  21. Smoking Status

  22. Medical History * 441 (4.1%) women with “hard” CHD events prior to enrollment (> 6mos)

  23. CHD Risk Status at Entry

  24. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N Mean SD N Mean SD Age (yrs) at screening 5310 63.6 7.3 5429 63.6 7.3 BMI (kg/m2) 5281 30.1 6.1 5391 30.1 6.2 Systolic BP (mm Hg) 5310 130.4 17.5 5429 130.2 17.6 Diastolic BP (mm Hg) 5310 76.5 9.2 5429 76.5 9.4

  25. CEE Placebo N % N % Ethnicity White 4007 75.5 4075 75.1 Black 782 14.7 835 15.4 Hispanic 322 6.1 333 6.1 American Indian 41 0.8 34 0.6 Asian/Pacific Islander 86 1.6 78 1.4 Unknown 72 1.4 74 1.4 Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment

  26. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N % N % Treated diabetes 410 7.7 411 7.6 Treated for hypertension 2386 48.0 2387 47.4 or BP > 140/90 High cholesterol 694 14.5 766 15.9 requiring pills Statin use at baseline 394 7.4 427 7.9 Aspirin (>80mg) use 1030 19.4 1069 19.7 at baseline

  27. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N % N % History of MI 165 3.1 172 3.2 History of angina 308 5.8 306 5.7 History of CABG/PTCA 120 2.3 114 2.1 History of stroke 76 1.4 92 1.7 History of DVT or PE 87 1.6 84 1.5

  28. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N % N % Hormone use Never 2769 52.2 2770 51.1 Past 1871 35.2 1948 35.9 Current 669 12.6 708 13.0 Duration of prior hormone use (years) <5 1352 53.2 1412 53.1 5 - 10 469 18.5 515 19.4 10+ 720 28.3 732 27.5

  29. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N % N % Parity Never pregnant / 489 9.3 461 8.5 no term pregnancy >1 term pregnancy 4779 90.7 4932 91.5 Age at first birth <20 1193 28.1 1234 28.0 20 - 29 2846 67.0 2914 66.1 30+ 210 4.9 260 5.9

  30. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N % N % Female relative had 893 18.0 870 17.1 breast cancer

  31. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N % N % Fracture at age 55+ 676 14.0 643 13.2 Falls in last 12 months 0 3300 67.0 3230 64.8 1 975 19.8 1024 20.5 2 422 8.6 478 9.6 3 or more 231 4.7 255 5.1

  32. Cumulative Drop-out and Drop-in Rates by Randomization Assignment and Follow-up Time

  33. Intermediate Outcomes

  34. Lipid Levels (8.6% subsample) Percent change, 1 yr

  35. Clinical Outcomes

  36. CEE and Coronary Heart Disease Events (Annualized %) by randomization assignment 95% CI CEE Placebo Hazard Ratio Nominal Adjusted * CHD † 177 (0.49%) 199 (0.54%) 0.91 (0.75,1.12) (0.72,1.15) CHD Death 54 (0.15%) 59 (0.16%) 0.94 (0.65,1.36) (0.54,1.63) Non-fatal MI 132 (0.37%) 153 (0.41%) 0.89 (0.70,1.12) (0.63,1.26) * Adjusted for multiple comparisons across time (OBF procedures). A Bonferroni adjustment for 6 outcomes was applied to all outcomes other than CHD, Breast Cancer and the global Index. † CHD includes acute MI requiring hospitalization, silent MI determined from serial electrocardiograms and coronary deaths. There were 14 silent MIs.

  37. Kaplan-Meier Estimates of Cumulative Hazards for CHD CHD HR, 0.91 95% nCI, 0.75-1.12

  38. CHD events by years since randomization P-value for trend with time, 0.02.

  39. Risk of CHD events by prior disease

  40. CEE and Stroke Events (Annualized %) By randomization assignment 95% CI CEE Placebo Hazard Ratio Nominal Adjusted Stroke 158 (0.44%) 118 (0.32%) 1.39 (1.10,1.77) (0.97,1.99) Fatal stoke 15 (0.04%) 14 (0.04%) 1.13 (0.54,2.34) (0.38,3.36) Non-fatal stroke 114 (0.32%) 85 (0.23%) 1.39 (1.05,1.84) (0.91,2.12)

  41. Kaplan-Meier Estimates of Cumulative Hazards for Stroke Stroke HR, 1.39 95% nCI, 1.10-1.77

  42. Risk of stroke by prior disease

  43. CEE and Venous Thromboembolic Events (Annualized %) By randomization assignment 95% CI CEE Placebo Hazard Ratio Nominal Adjusted VTE† 101 (0.28%) 78 (0.21%) 1.33 (0.99,1.79) (0.86,2.08) DVT† 77 (0.21%) 54 (0.15%) 1.47 (1.04,2.08) (0.87,2.47) PE† 48 (0.13%) 37 (0.10%) 1.34 (0.87,2.06) (0.70,2.55) † VTE, venous thromboembolic disease; DVT, deep vein thrombosis; PE, pulmonary embolism

  44. Kaplan-Meier Estimates of Cumulative Hazards for PE PE HR, 1.34 95% nCI 0.87-2.06

  45. CEE and Cardiovascular Disease Events (Annualized %) By randomization assignment 95% CI CEE Placebo Hazard Ratio Nominal Adjusted Total CVD 811 (2.25%) 746 (2.01%) 1.12 (1.01,1.24) (0.97,1.30)

  46. CEE and Cancer Incidence (Annualized %) By randomization assignment 95% CI CEE Placebo Hazard Ratio Nominal Adjusted Invasive breast 94 (0.26%) 124 (0.33%) 0.77 (0.59,1.01) (0.57,1.06)cancer Colorectal cancer 61 (0.17%) 58 (0.16%) 1.08 (0.75,1.55) (0.63,1.86) Total cancer 372 (1.03%) 408 (1.10%) 0.93 (0.81,1.07) (0.75,1.15)

  47. Kaplan-Meier Estimates of Cumulative Hazards for Breast Cancer Invasive Breast Cancer HR, 0.77 95% nCI, 0.59-1.01

  48. Kaplan-Meier Estimates of Cumulative Hazards for Colorectal Cancer Colorectal Cancer HR, 1.08 95% nCI, 0.75-1.55

  49. CEE and Fracture Events (Annualized %) By randomization assignment 95% CI CEE Placebo Hazard Ratio Nominal Adjusted Hip fracture 38 (0.11%) 64 (0.17%) 0.61 (0.41,0.91) (0.33,1.11) Vertebral fracture 39 (0.11%) 64 (0.17%) 0.62 (0.42,0.93) (0.34,1.13) Total fracture 503 (1.39%) 724 (1.95%) 0.70 (0.63,0.79) (0.59,0.83)

More Related